Excessive or unregulated production of tumor necrosis factor α, or TNFα, has been implicated in a number of disease conditions. These include endotoxemia and/or toxic shock syndrome (Tracey et al., Nature 330, 662-664 (1987) and Hinshaw et al., Circ. Shock 30, 279-292 (1990)), cachexia (Dezube et al., Lancet 335 (8690), 662 (1990)), and Adult Respiratory Distress Syndrome (Millar et al., Lancet 2 (8665), 712-714 (1989)). Certain substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines have been shown to reduce levels of TNFα (International Publication No. WO 98/03502, incorporated herein by reference in its entirety).
An oxoisoindoline that has demonstrated particular therapeutic promise is 3-(4-amino-1-oxoisoindolin-2-yl)-piperidine-2,6-dione (REVLIMID™). This compound has been shown to be useful in treating and preventing a wide range of diseases and conditions including, but not limited to, inflammatory diseases, autoimmune diseases, and cancers including both solid and homological cancers. REVLIMID has received Fast Track Designation from the Food and Drug Administration for the treatment of multiple myeloma and myelodysplastic syndromes. Furthermore, REVLIMID is in late-stage clinical trials for the treatment of hematological and solid tumor cancers and immunological and inflammatory diseases.
Existing methods for synthesizing substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines are described in International Publication No. WO 98/03502 (See page 7, line 22, to page 10, line 33, and Examples 1 to 18) and Muller et al., Bioorgan. Med. Chem. Lett. 9, 1625-1630 (1999). In one existing method, an N-protected glutamine is cyclized and then deprotected to generate an α-aminoglutarimide hydrochloride. The α-aminoglutarimide hydrochloride is coupled to a substituted methyl 2-bromomethylbenzoate to form a 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline. A benzo substituent can then be transformed to another substituent if desired.
While these methods are enabling and useful for preparing substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines, there are possibilities for alterations that may result in a more efficient synthesis.
Citation of any reference in Section 2 of this application is not to be construed as an admission that such reference is prior art to the present application.